Working in tandem with two other major laboratory lobbying groups, the American College of Medical Genetics and Genomics (ACMG) earlier this month released guidelines to better determine the disease-causing potential of specific DNA sequence variations. The guidelines, which were released by ACMG with the College of American Pathologists, and the Association for Molecular Pathology, are intended to create a more uniform system of classifying genetic variants and their potential to cause harm. The new system took some 24 months to develop, ACMG officials said, and included not only a working group but a variety of public forums at ACMG and other group events. Such updates were required given the wide variability in how genetic makeup can create or influence a particular genetic condition. As a result, clinicians are often challenged juggling the genetic variants in tandem with their clinical validity and the actions required to address any health care issues. Indeed, the new guidelines only cover inherited variants, not those that may occur within cells of a cancer tumor, which create treatment challenges of their own. The new guidelines include five different classifications: “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign,” along with standard definitions for each term. That […]
Working in tandem with two other major laboratory lobbying groups, the American College of Medical Genetics and Genomics (ACMG) earlier this month released guidelines to better determine the disease-causing potential of specific DNA sequence variations.
The guidelines, which were released by ACMG with the College of American Pathologists, and the Association for Molecular Pathology, are intended to create a more uniform system of classifying genetic variants and their potential to cause harm.
The new system took some 24 months to develop, ACMG officials said, and included not only a working group but a variety of public forums at ACMG and other group events.
Such updates were required given the wide variability in how genetic makeup can create or influence a particular genetic condition. As a result, clinicians are often challenged juggling the genetic variants in tandem with their clinical validity and the actions required to address any health care issues. Indeed, the new guidelines only cover inherited variants, not those that may occur within cells of a cancer tumor, which create treatment challenges of their own. The new guidelines include five different classifications: “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign,” along with standard definitions for each term.
That still may not be enough for the medical community to wrap its arms around all the gene variants and their impact on health care. The variants that can lead to sickle cell disease are contained in everyone’s genetic makeup. But among the CFTR gene that is linked to cystic fibrosis, ACMG officials said there are more than 150 variants that can have an impact on how that gene functions, and more than 1,000 others where the impact is still uncertain.
“These updated guidelines provide a systematic and sound way to classify genomic variants so that when Lab A on the east coast and Lab B on the west coast are reporting results, they are using the same method to classify that variant,” said Sue Richards, who chaired the workgroup that developed the guidelines, in a press release. She serves as medical director of the Knight Diagnostic Laboratories, and is a professor of molecular and medical genetics at Oregon Health & Science University in Portland.
Some laboratories have been sharing the genetic variations and accompanying data through a public domain database known as ClinVar, but it is relatively new and not all laboratories are posting data.
“In the past, standard terms such as ‘pathogenic’ and a consistent strategy for classifying variants have been lacking, leading to wide variation in how laboratories classify individual differences in DNA sequence,” Richards said in the release.
However, the ACMG cautioned that making a diagnosis should not be done with the molecular data alone. For example, a classification of “likely pathogenic” would provide enough evidence for a physician to act if it’s combined with prenatal ultrasound, enzyme assays, physical findings or imaging studies.
Takeaway: The laboratory and pathology communities believe the advances in sequencing technology require commensurate updates in classifications of genetic variants.
